In our exploration of T2D risk as a function of 23 polymorphic IRS1 variants on the HumanCVD BeadChip using data from WHII [12,15], with follow-up genotyping in other study cohorts, we found evidence for a possible independent effect on risk of a genetic variant in the 5′-flanking region of IRS1 (rs6725556; −3538A > G), although no test met our prespecified criteria of p < 0.01 for statistical significance. This evidence concerns the gene IRS1 and type 2 diabetes mellitus.